Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia by blocking neurotransmission at the NMDA-type glutamate receptor. The ability of NMDA antagonists to induce schizophrenia-like symptoms indicates that endogenous NMDA receptor dysfunction or dysregulation may contribute substantially to the pathophysiology of schizophrenia. This K02 award will enable the candidate to pursue investigations directed to the continued development of the PCP/NMDA model of schizophrenia. Specific projects will include: 1) characterization of neurophysiological and neurocognitive dysfunction in schizophrenia relative to the predictions of the PCP/NMDA model, 2) investigation of mechanisms underlying neurophysiological and neurocognitive dysfunction in schizophrenia using multichannel intracortical recordings in monkeys, 3) determination of the effects of NMDA augmenting agents on negative symptoms and cognitive functioning in schizophrenia, and 4) development of novel, clinically relevant NMDA augmentation strategies. Neurophysiological studies will focus on impaired generation of mismatch negativity (MMN) and other cognitive event-related potential (ERP) in schizophrenia. Treatment studies will focus on the clinical use of glycine and characterization of preclinical effects of glycine precursors and/or reuptake inhibitors on rodent behavior and free extracellular glycine levels. The research will build upon studies currently supported by NIH research and career development awards to the candidate. Over the past several years, the candidate has acquired expertise in PCP/NMDA neuropharmacology and in the application neurophysiological methods to the analysis of brain dysfunction in schizophrenia, and has gained experience in clinical psychopharmacology research in schizophrenia. This award will permit the candidate to develop further expertise in neurophysiology and psychopharmacology and to obtain exposure and experience in the use of structural and functional neuroimaging in schizophrenia.